Estrogens have been recognized as being important for promoting the growth of a large proportion of breast cancers. Over half of all breast cancers overexpress estrogen receptor alpha (ERα) and around 70% of these respond to anti-estrogen therapy. However, there are some ERα-positive tumors that do not respond to therapy and eventually become resistant. Now, researchers at the University of California, San Francisco (UCSF), have gained insight into how they may be doing this.
Their findings are published in the journal Cell in a paper titled, “ERα is an RNA-binding protein sustaining tumor cell survival and drug resistance,” and demonstrate how ERα aids malignant cells in overcoming innate anticancer mechanisms and develop resistance.
“ERα is a hormone receptor and key driver for over 70% of breast cancers that has been studied for decades as a transcription factor,” the researchers wrote.
“Unexpectedly, we discover that ERα is a potent non-canonical RNA-binding protein. We show that ERα RNA binding function is uncoupled from its activity to bind DNA and critical for breast cancer progression. Employing genome-wide cross-linking immunoprecipitation (CLIP) sequencing and a functional CRISPRi screen, we find that ERα-associated mRNAs sustain cancer cell fitness and elicit cellular responses to stress. Mechanistically, ERα controls different steps of RNA metabolism.”
Yichen Xu, PhD, a postdoctoral fellow in urology at UCSF and the first author of the study explained, “The RNA-centric function of the estrogen receptor has so far been hidden behind its well-established role as a transcription factor, and may have been supporting cancer progression on the sly.”
The researchers observed how ERα tends to bind to RNAs, particularly messenger RNAs (mRNAs) involved in cancer progression.
“Cancer cells are constantly being exposed to stress, and these cells have learned to live with it,” explained Davide Ruggero, PhD, the senior author of the study, a professor of urology, and the Helen Diller Family endowed chair in basic research at UCSF. “Many compounds used to kill cancer induce stress in the cancer, and most of the cancer cells die. But some eventually find a way to bypass the stress induced by the therapy.”
Ruggero’s team analyzed cancer cells from 14 patients diagnosed with ERα-positive breast cancer and found they had elevated levels of ERα mRNA targets.
The researchers then investigated breast cancer cell lines that had acquired resistance to tamoxifen, a hormone therapy for breast cancer, both in tissue culture and in mouse xenografts.
The researchers observed inhibiting the ERα RNA-binding activity restored tamoxifen’s potency against the tumors in mice. It also made the cells in culture more sensitive to stress and apoptosis.
Although further research is needed, the findings give a better understanding of ERα positive tumors and pave the way for further studies and improved treatment to overcome drug resistance.
“One of the reasons why we haven’t cured cancer is because we still don’t fully understand how it works,” Ruggero said. “If we start from the most basic point of view, we might be able to discover new things.”